This invention relates to the purification of complex reaction mixtures to obtain high purity (&gt;98%) isothiazolones by first forming and isolating readily filterable high purity crystalline salts of the isothiazolones of the formula: ##STR1## wherein R is hydrogen or methyl and Y is a linear or branched alkyl of from 3 to 10 carbon atoms, followed by hydrolysis with water to the desired isothiazolones which are well known biocides.
A process for preparing isothiazolone reaction mixtures is described in U.S. Pat. No. 3,761,488, where a N,N'-disubstituted 3,3'-dithiodipropionamide is halogenated and cyclized with such reactants as chlorine or sulfuryl chloride to acrude reaction mixture containing 2-substituted-3-isothiazolone hydrohalide salt in solution. The halogenation reactant is maintained at about 3 equivalents of halogen per equivalent of dithiodiamide to obtain a complete reaction which unfortunately contains small to significant amount of unwanted products such as 5-halo-2-substituted isothiazolone, 4-halo-2-substituted isothiazolone, 4,5-dihalo- 2-substituted isothiazolone, 3-halo-N-substituted alkyl propionamide, and other amide impurities. From the reaction mixture the hydrohalide salt is crystallized, isolated and then hydrolyzed with water to the desired isothiazolone of high purity (&gt;98%).
An alternate route to isothiazolones is disclosed in European Patent 95,907, wherein a 3-mercaptopropionamide is treated with at least about 2 equivalents of chlorine or other halogenating agent to form and isolate the isothiazolone hydrohalide salt, followed by its hydrolysis to obtain the desired isothiazolone.
Both of the above processes are also useful in preparing the 4-methyl-2-substituted isothiazolones from the corresponding mercaptoisobutyramide or dithiodiisobutyramide intermediate.
However, in these processes some amounts of above mentioned impurities are formed. For improvement of product quality, safety reasons, and for many end uses, it is desirable to remove such impurities.
The materials to be chlorinated and cyclized to the corresponding isothiazolone hydrochloride containing reaction mixture have the following formula: ##STR2## Some solvents used to conduct the chlorination/cyclization has been a lower alkyl ester, such as ethyl acetate, butyl acetate, and the like. Upon removal of the excess hydrogen chloride, the isothiazolone salt precipitates. There are disadvantages to using such solvents because:
a. certain impurities precipitate with the desired product and be removed only with difficulty;
b. the solvent gets hydrolyzed during the hydrolysis of the isothiazolone salt, leading to a loss of solvent on recovery or introduction of the hydrolyzed solvent as an impurity in the desired product;
c. upon recycle the solvent or its hydrolysed products react during the chlorination/cyclization step to lower product yield and have deleteriously affect; or
d. the desired hydrochloride salt may be more soluble in the ester solvent to cause significant yield losses.
It is an object of this invention to provide a suitable solvent for the chlorination reaction and subsequent isothiazolone purification which is inert to chlorination under the reaction conditions, inert to the hydrolysis reaction conditions employed to hydrolyse the salt, sufficiently volatile to be removed completely from the isothiazolone when desired, and possessing such solubility characteristics for the isothiazolone salt allowing quantitative separation of pure salt after removal of excess hydrogen chloride. It is a further object to provide processing conditions for the crystallization which produce pure clustered crystal aggregates of a size and shape suitable for ease of filtration and washing, and which avoid forming secondary nucleation tiny crystals which clog filtration apparatus and are difficult to free from mother liquor containing reaction impurities.
European Patent 95,907 teaches other solvents may be used, such as toluene or perchloroethylene. These solvents are reactive under halogenation conditions or are toxic or create environmental problems.
European Patent Application 271,761, teaches purification of crude isothiazolones, by isolation of the isothiazolone (not the hydrochloride) and process impurities (in an unspecified procedure), dissolving this material in an organic solvent immiscible with water, treating this solution with a strong acid, such as hydrogen chloride, to form the salt, followed by separation and hydrolysis of the salt in the presence of the organic solvent. Monochlorobenzene and chlorinated hydrocarbons are mentioned as solvents, but are not used. There is no teaching in this reference which would lead one to the present invention.